Brand Names: U.S.

Navelbine

Pharmacologic Category

Antineoplastic Agent, Antimicrotubular

Antineoplastic Agent, Vinca Alkaloid

Pharmacology

Vinorelbine is a semisynthetic vinca alkaloid which binds to tubulin and inhibits microtubule formation, therefore, arresting the cell at metaphase by disrupting the formation of the mitotic spindle; it is specific for the M and S phases. Vinorelbine may also interfere with nucleic acid and protein synthesis by blocking glutamic acid utilization.

Protein Binding

Use: Labeled Indications

Off Label Uses

Breast cancer, metastatic

Data from two prospective multicenter randomized trials evaluating the use of vinorelbine in patients with HER-2 positive advanced or metastatic breast cancer supports the use of vinorelbine in the treatment of this condition [Andersson 2011], [ Burstein 2007]. Data from two phase II studies also demonstrated activity of vinorelbine in the treatment of metastatic breast cancer unresponsive to anthracyclines, taxanes, and vinorelbine (in combination with trastuzumab) for the treatment of metastatic breast cancer without prior chemotherapy [Zelek 2001], [Burstein 2001].

Cervical cancer, persistent or recurrent

Data from a phase II study evaluating the use of vinorelbine in patients with advanced or recurrent squamous cell carcinoma of the cervix refractory to standard chemotherapy supports the use of vinorelbine in this condition [Muggia 2004]. Data from a phase II study evaluating the use of vinorelbine in patients with recurrent or persistent nonsquamous cell carcinoma of the cervix who had received prior chemotherapy also supports the use of vinorelbine for this condition [Muggia 2005]. Additional trials may be necessary to further define the role of vinorelbine in the treatment of persistent or recurrent cervical cancer.

Hodgkin lymphoma, relapsed or refractory (GVD regimen)

Data from a phase I/II trial evaluating the use of vinorelbine (in combination with gemcitabine and doxorubicin) in patients with relapsed or refractory Hodgkin lymphoma supports the use of vinorelbine for the treatment of this condition [Bartlett 2007]. Additional trials may be necessary to further define the role of vinorelbine (GVD regimen) in the treatment of relapsed or refractory Hodgkin lymphoma.

Hodgkin lymphoma, relapsed or refractory (IGEV regimen)

Data from a prospective study evaluating the use of vinorelbine (in combination with ifosfamide and gemcitabine) in patients with relapsed or refractory Hodgkin lymphoma supports the use of vinorelbine for the treatment of this condition [Santoro 2007]. Additional trials may be necessary to further define the role of vinorelbine (IGEV regimen) in the treatment of relapsed or refractory Hodgkin lymphoma.

Malignant pleural mesothelioma

Data from a phase II open-label study evaluating the use of vinorelbine in patients with relapsed malignant pleural mesothelioma suggests that vinorelbine may be beneficial for the treatment of this condition [Stebbing 2009]. Additional trials may be necessary to further define the role of vinorelbine in the treatment of malignant pleural mesothelioma.

Data from a multicenter randomized controlled trial in patients with recently diagnosed malignant pleural mesothelioma demonstrated that adding vinorelbine to active symptom control offers no significant benefit; however, the authors determined, based on exploratory analyses, that the role of vinorelbine deserves further investigation [Muers 2008].

Ovarian cancer, relapsed

Data from two phase II studies evaluated the use of vinorelbine in patients with recurrent or resistant epithelial ovarian cancer (after treatment with platinum and/or taxane) suggests that vinorelbine may be beneficial for the treatment of this condition [Bajetta 1996], [Rothenberg 2004]. Additional trials may be necessary to further define the role of vinorelbine in this condition.

Salivary gland cancer, recurrent

Data from a phase II randomized study evaluating the use of vinorelbine (in combination with cisplatin or monotherapy) in patients with recurrent salivary gland cancer supports the use of vinorelbine for this condition [Airoldi 2001]. Additional trials may be necessary to further define the role of vinorelbine in the treatment of patients with recurrent salivary gland cancer.

Small cell lung cancer, refractory

Data from two phase II studies evaluating the use of vinorelbine in patients with treatment refractory small cell lung cancer supports the use of vinorelbine for the treatment of this condition [Furuse 1996], [Jassem 1993]. Additional trials may be necessary to further define the role of vinorelbine in the treatment of patients with refractory small cell lung cancer.

Soft tissue sarcoma, advanced

Data from a phase II randomized study evaluating the use of vinorelbine (in combination with gemcitabine) in patients with unresectable or metastatic soft -tissue sarcomas supports the use of vinorelbine in the treatment of this condition [Dileo 2007]. Additional trials may be necessary to further define the role of vinorelbine in the treatment of patients with advanced soft tissue sarcoma.

Contraindications

Pretreatment granulocyte counts <1000/mm3

Dosing: Adult

Non-small cell lung cancer (NSCLC): IV:

Single-agent therapy: 30 mg/m2 every 7 days until disease progression or unacceptable toxicity

Combination therapy: 25 to 30 mg/m2 every 7 days (in combination with cisplatin)

Off-label dosing: 25 mg/m2 days 1 and 8 every 21 days (in combination with cisplatin and cetuximab) for up to 6 cycles (Pirker 2009) or 25 to 30 mg/m2 days 1, 8, and 15 every 28 days (in combination with gemcitabine) for 6 cycles or until disease progression or unacceptable toxicity (Herbst 2002; Greco 2007)

Breast cancer, metastatic (off-label use): IV: 25 mg/m2 every 7 days (as a single agent) until disease progression or unacceptable toxicity (Zelek 2001) or 30 mg/m2 every 7 days (as a single agent); after 13 weeks, may administer every 14 days for patient convenience, continue until disease progression or unacceptable toxicity (Vogel 1999) or 25 mg/m2 every 7 days (in combination with trastuzumab) until disease progression or unacceptable toxicity (Burstein 2001; Burstein 2007) or 30 or 35 mg/m2 days 1 and 8 every 21 days (in combination with trastuzumab) until disease progression or unacceptable toxicity (Andersson 2011)

Salivary gland cancer, recurrent (off-label use): IV: 25 mg/m2 on days 1 and 8 of a 21-day cycle (in combination with cisplatin) for a minimum of 3 cycles and for up to 6 cycles (Airoldi 2001) or 30 mg/m2 every 7 days (monotherapy) for a minimum of 9 weeks and for up to 6 cycles (Airoldi 2001)

Dosing: Renal Impairment

Dosing: Hepatic Impairment

Note: In patients with concurrent hematologic toxicity and hepatic impairment, administer the lower of the doses determined from the adjustment recommendations.

Administer with caution in patients with hepatic insufficiency. In patients who develop hyperbilirubinemia during treatment with vinorelbine, the dose should be adjusted for total bilirubin as follows:

Granulocytes ≥1,500 cells/mm3 on day of treatment: Administer 100% of starting dose.

Granulocytes 1,000 to 1,499 cells/mm3 on day of treatment: Administer 50% of starting dose.

Granulocytes <1,000 cells/mm3 on day of treatment: Do not administer. Repeat granulocyte count in 1 week. If 3 consecutive doses are held because granulocyte count is <1,000 cells/mm3, discontinue vinorelbine.

Adjustment: For patients who, during treatment, have experienced fever or sepsis while granulocytopenic or had 2 consecutive weekly doses held due to granulocytopenia, subsequent doses of vinorelbine should be:

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

Reconstitution

Dilute in D5W or NS to a final concentration of 1.5-3 mg/mL (for syringe) or D5W, NS, 1/2NS, D51/2NS, LR, or Ringer's to a final concentration of 0.5 to 2 mg/mL (for IV bag). Vinorelbine should NOT be prepared during the preparation of any intrathecal medications.

Administration

For IV use only; FATAL IF GIVEN INTRATHECALLY. Administer as a direct intravenous push or rapid bolus, over 6 to 10 minutes (up to 30 minutes). Longer infusions may increase the risk of pain and phlebitis. Intravenous doses should be followed by at least 75 to 125 mL of saline or D5W to reduce the incidence of phlebitis and inflammation.

Storage

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Intact vials are stable at room temperature of 25°C (77°F) for up to 72 hours. Solutions diluted for infusion in polypropylene syringes (D5W or NS) or polyvinyl chloride bags (D5W, NS, 1/2NS, D51/2NS, LR, or Ringer's) are stable for 24 hours at 5°C to 30°C (41°F to 86°F). After preparation, keep vinorelbine in a location away from the separate storage location recommended for intrathecal medications.

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Macrolide Antibiotics: May increase the serum concentration of Antineoplastic Agents (Vinca Alkaloids). Macrolides may also increase the distribution of Vinca Alkaloids into certain cells and/or tissues. Management: Consider an alternative to using a macrolide antibiotic when possible in order to avoid the potential for increased vinca alkaloid toxicity. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

ALERT: U.S. Boxed Warning

Experienced physician:

Vinorelbine tartrate injection should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.

Not for intrathecal use:

This product is for intravenous (IV) use only. Intrathecal administration of other vinca alkaloids has resulted in death. Syringes containing this product should be labeled “Warning — for IV use only. Fatal if given intrathecally.”

Bone marrow suppression:

Severe granulocytopenia resulting in increased susceptibility to infection may occur. Granulocyte counts should be greater than or equal to 1000 cells/mm3 prior to the administration of vinorelbine tartrate. The dosage should be adjusted according to complete blood counts with differentials obtained on the day of treatment.

Extravasation:

It is extremely important that the IV's needle or catheter be properly positioned before vinorelbine tartrate is injected. Administration of vinorelbine tartrate may result in extravasation causing local tissue necrosis or thrombophlebitis.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Severe granulocytopenia may occur with treatment (may lead to infection); granulocyte counts should be ≥1000 cells/mm3 prior to treatment initiation; dosage adjustment may be required based on blood counts (monitor blood counts prior to each dose). Granulocytopenia is a dose-limiting toxicity; nadir is generally 7 to 10 days after administration and recovery occurs within the following 7 to 14 days. Monitor closely for infections and/or fever in patients with severe granulocytopenia. Use with extreme caution in patients with compromised marrow reserve due to prior chemotherapy or radiation therapy.

• Neuropathy: May cause new-onset or worsening of pre-existing neuropathy; use with caution in patients with neuropathy. Monitor for new or worsening sign/symptoms of neuropathy. Dosage adjustment required.

• Pulmonary toxicity: Fatal cases of interstitial pulmonary changes and ARDS have been reported with single-agent therapy (mean onset of symptoms: 1 week). Promptly evaluate changes in baseline pulmonary symptoms or any new-onset pulmonary symptoms (eg, dyspnea, cough, hypoxia). Acute shortness of breath and severe bronchospasm have been reported with vinca alkaloids, usually when used in combination with mitomycin.

Disease-related concerns:

• Hepatic impairment: Vinorelbine elimination is predominantly hepatic. While there is no evidence that toxicity is enhanced in patients with elevated transaminases, use with caution in patients with severe hepatic injury or impairment; dosage modification required for elevated total bilirubin.

• Radiation therapy: May have radiosensitizing effects with prior or concurrent radiation therapy; radiation recall reactions may occur in patients who have received prior radiation therapy.

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

• NOT for intrathecal use: [US Boxed Warning]: For IV use only; intrathecal administration of other vinca alkaloids has resulted in death. If dispensed in a syringe, should be labeled “for intravenous use only - fatal if given intrathecally". Vinorelbine should NOT be prepared during the preparation of any intrathecal medications. After preparation, keep vinorelbine in a location away from the separate storage location recommended for intrathecal medications.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.